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Proteins are the key players that regulate cellular structure and function. DNA, which functions as the blueprint for protein synthesis, is first transcribed into a messenger RNA (mRNA), which is further read and translated into a polypeptide chain (a “new-born” protein) by macromolecular machines called ribosomes. Here, the ribosome essentially functions as a tunnel through which the train of mRNA passes and within which amino acids are assembled in a sequential manner depending on the mRNA sequences to form a polypeptide.
Certain intrinsic sequences in the polypeptide can, however, trigger premature termination of translation. As protein synthesis is an essential cellular process, this event can pose a great risk, resulting in protein dysfunction or synthesis of incomplete proteins. In nascent (newly synthesized) polypeptides, this interrupting sequence, which is rich in negatively charged amino acid residues, is known as an “intrinsic ribosome destabilization” (IRD) sequence. With such sequences scattered across the genome, how do cells avoid such a premature termination and ensure uninterrupted translation?
A team of researchers from the Tokyo Tech, led by Professor Hideki Taguchi have now answered this key question in their recently published The EMBO Journal article. “The need for a tunnel structure is not clear, given that the primary function of the ribosome is simply to polymerize amino acids into a polypeptide. The tunnel architecture, which spans 30 to 40 nascent polypeptides in length, may have evolved to balance the stabilization and obstacles of translation elongation.” explains Prof. Taguchi.
The researchers began by analyzing the proteome wide profile of the bacterial model system, Escherichia coli, and identified IRD sequences across various proteins. By constructing sequences of varying lengths preceding the IRD motifs, they were able to show that the peptide sequences that span the ribosomal tunnel can counteract destabilization by the IRD sequence in a length-dependent but sequence-independent manner. They further noted that longer sequences were associated with better IRD lowering efficiency.
Next, they went on to investigate how properties of amino acid residues in the nascent polypeptide and their distribution across the proteome influence IRD. Using various amino acid substitutions preceding the IRD sequence, they found that residues with bulkier side chains were able to prevent IRD more effectively than did smaller ones. Further, they observed a bias in the sequence of amino acids across the proteome. Interestingly, open reading frames that code for proteins were enriched in bulkier amino acid residues towards the N-terminal regions that are translated first. The researchers speculate that these bulky residues occupy the entry of the ribosomal exit site, thereby stabilizing the translating machinery by bridging the small and large ribosomal subunits. Further, on abrogating specific proteins in the ribosomal exit tunnel they found an increase in IRD, suggesting that interactions between the nascent peptide and ribosomal proteins contribute to translation continuity.
Together, these findings indicate an intrinsic regulatory mechanism wherein the nascent peptide in collaboration with the ribosomal tunnel helps maintain ribosomal stability and continuity in translation elongation.
Prof. Taguchi concludes by saying, “Our findings highlight a positive feedback system wherein the ribosomal tunnel is occupied by its own product for uninterrupted translation. We report on the role of nascent peptide chains within the ribosomal exit tunnel in ensuring efficient protein synthesis.”
The quest for stability seems to have deep sub-cellular roots.
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In the first study of its kind, researchers from Sanford Burnham Prebys have uncovered molecular changes within the aging brains of individuals with Down syndrome that could help explain their cognitive challenges, including the uniform development of Alzheimer’s disease in these individuals later in life. The findings, published in the Proceedings of the National Academy of Science, could help pave the way for new therapies to aid people with Down syndrome and Alzheimer’s disease.
“A stunningly high level of molecular and cellular diversity was found affecting single brain cells, which provides new avenues for understanding both Down syndrome and Alzheimer’s disease,” says senior author Jerold Chun, M.D., Ph.D., professor and senior vice president of Neuroscience Drug Discovery at Sanford Burnham Prebys.
An old question requires new techniques
Down syndrome, also known as trisomy 21, occurs when the body has an extra copy of human chromosome 21, resulting in three copies instead of the usual two. Occurring in about one in 700 births, it is the most common chromosomal disorder. In addition to their lifelong cognitive challenges, all people with Down syndrome are exceptionally vulnerable to neurodegeneration later in life.
“By the time they’re in their 40s, every single person with Down syndrome will experience some Alzheimer’s pathology,” Chun says. “We asked what happens in the brain before Alzheimer’s disease takes hold.”
While some of the genes and biochemical pathways involved in the development of Alzheimer’s in people with Down syndrome have been identified, the bigger picture — the cellular and molecular changes that are responsible for triggering these pathways — remains a mystery.

A team led by investigators at Massachusetts General Hospital (MGH) has shown that people living with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, who carry a mutation in the C9orf72 gene exhibit elevated levels of tau and phosphorylated tau protein in the motor cortex region of the brain. The research, which is published in Brain Pathology, also identified new genetic mutations in the tau gene and revealed that the ratio of different forms of tau protein may be an indicator of disease progression in ALS.
“This study focused on tau, a protein that is critical for stabilizing the structure of nerve cells and has been implicated in Alzheimer’s disease, and whether it plays a role in ALS pathogenesis as it can form aggregates and lead to cellular dysfunction in a number of neurodegenerative disorders,” says senior author Ghazaleh Sadri-Vakili, PhD, director of the NeuroEpigenetics Laboratory at the MassGeneral Institute for Neurodegenerative Disease and the Sean M. Healey and AMG Center for ALS at Mass General.
Using post-mortem brain samples from people with ALS, the researchers discovered that tau and one of its phosphorylated forms are increased in the brains of patients whose cells carry a mutation in the C9orf72 gene that was linked to ALS and dementia 10 years ago. “We also identified new genetic mutations in the tau gene that are specific to ALS and may have functional consequences that may exacerbate disease onset or progression,” says Sadri-Vakili.
To determine if tau protein is a viable biomarker for ALS, the team measured tau and its phosphorylated form in cerebrospinal fluid from people living with ALS. The investigators demonstrated that increases in these particular forms of tau protein in patients’ cerebrospinal fluid correlated with disease progression. Therefore, tau levels — and specifically the ratio between tau and the phosphorylated form of the tau protein — might help clinicians predict patients’ rate of disease progression. “These findings are exciting as there is an unmet and urgent need for disease biomarkers in ALS,” notes Sadri-Vakili.
Co-authors include Tiziana Petrozziello, Ana C. Amaral, Simon Dujardin, Sali M.K. Farhan, James Chan, Bianca A. Trombetta, Pia Kivisäkk, Alexandra N. Mills, Evan A. Bordt, Spencer E. Kim, Patrick M. Dooley, Caitlin Commins, Theresa R. Connors, Derek H. Oakley, Anubrata Ghosal, Teresa Gomez-Isla, Bradley T. Hyman, Steven E. Arnold, Tara Spires-Jones, Merit E. Cudkowicz, and James D. Berry.
Funding was provided by the Judith and Jean Pape Adams Charitable Foundation, the Byrne Family Endowed Fellowship in ALS Research, the Alzheimer’s Association, the Jack Satter Foundation, and the National Institute on Aging.
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UBC researchers have trained computers to predict the next designer drugs before they are even on the market, technology that could save lives.
Law enforcement agencies are in a race to identify and regulate new versions of dangerous psychoactive drugs such as bath salts and synthetic opioids, even as clandestine chemists work to synthesize and distribute new molecules with the same psychoactive effects as classical drugs of abuse.
Identifying these so-called “legal highs” within seized pills or powders can take months, during which time thousands of people may have already used a new designer drug.
But new research is already helping law enforcement agencies around the world to cut identification time down from months to days, crucial in the race to identify and regulate new versions of dangerous psychoactive drugs.
“The vast majority of these designer drugs have never been tested in humans and are completely unregulated. They are a major public health concern to emergency departments across the world,” says UBC medical student Dr. Michael Skinnider, who completed the research as a doctoral student at UBC’s Michael Smith Laboratories.
A Minority Report for new designer drugs
Dr. Skinnider and his colleagues used a database of known psychoactive substances contributed by forensic laboratories around the world to train an artificial intelligence algorithm on the structures of these drugs. The algorithm they used, known as a deep neural network, is inspired by the structure and function of the human brain.

A large analysis of health records from 87 health care centers across the United States found that people taking a class of antidepressants called selective serotonin reuptake inhibitors (SSRIs), particularly fluoxetine, were significantly less likely to die of COVID-19 than a matched control group.
The results add to a body of evidence indicating that SSRIs may have beneficial effects against the worst symptoms of COVID-19, although large randomized clinical trials are needed to prove this.
“We can’t tell if the drugs are causing these effects, but the statistical analysis is showing significant association,” said Marina Sirota, PhD, associate professor of pediatrics and a member of the Bakar Computational Health Sciences Institute (BCHSI) at UC San Francisco. “There’s power in the numbers.”
The UCSF-Stanford research team analyzed electronic health records from the Cerner Real World COVID-19 de-identified database, which had information from almost 500,000 patients across the U.S. This included 83,584 adult patients diagnosed with COVID-19 between January and September, 2020. Of those, 3,401 patients were prescribed SSRIs.
The large size of the dataset enabled researchers to compare the outcomes of patients with COVID-19 on SSRIs to a matched set of patients with COVID-19 who were not taking them, thus teasing out the effects of age, sex, race, ethnicity, and comorbidities associated with severe COVID-19, such as diabetes and heart disease, as well as the other medications the patients were taking.
The results showed that patients taking fluoxetine were 28 percent less likely to die; those taking either fluoxetine or another SSRI called fluvoxamine were 26 percent less likely to die; and the entire group of patients taking any kind of SSRI was 8 percent less likely to die than the matched patient controls.
Though the effects are smaller than those found in recent clinical trials of new antivirals developed by Pfizer and Merck, the researchers said more treatment options are still needed to help bring the pandemic to an end.
“The results are encouraging,” said Tomiko Oskotsky, MD, a research scientist in Sirota’s lab at BCHSI. “It’s important to find as many options as possible for treating any condition. A particular drug or treatment may not work or be well tolerated by everyone. Data from electronic medical records allow us to quickly look into existing drugs that could be repurposed for treating COVID-19 or other conditions.”
Other authors include David K. Stevenson, MD, Ivana Marić, PhD, Ronald J. Wong, PhD, and Nima Aghaeepour, PhD, of Stanford University; and Alice Tang and Boris Oskotsky, PhD, of UCSF.
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Materials provided by University of California – San Francisco. Original written by Laura Kurtzman. Note: Content may be edited for style and length.

New research led by the University of Bristol, has shown the drug losartan, normally used to treat high blood pressure (hypertension), is not effective in slowing down the progression of Alzheimer’s disease (AD) in people with mild-to-moderate disease after 12 months of treatment. However, the drug could still be of benefit if prescribed for longer and if given to people with very early disease. The findings are from the phase 2 multi-centre clinical trial known as RADAR ((Reducing pathology in Alzheimer’s Disease through Angiotensin taRgeting).
The double blinded placebo-controlled randomised trial (where participants and doctors don’t know what treatment people are on) investigated whether losartan, compared with a placebo, could reduce brain volume loss, as a measure of disease progression, in people clinically diagnosed with established AD.
The research, published in The Lancet Neurology and NIHR Efficacy and Mechanism Evaluation, is the first to evaluate the potential benefit of losartan, an angiotensin receptor blocker, which is a drug commonly used to treat high blood pressure and heart failure, in clinically diagnosed AD using brain imaging as a primary outcome.
Two-hundred and sixty-one people aged 55 years or older diagnosed with AD, who had not been prescribed similar hypertension drugs, and who had capacity to consent, were recruited from 23 UK National Health Service hospital trusts between 22 July 2014 and 17 May 2018.
The 211 eligible participants were then randomly allocated with 105 assigned to receive the study drug, 100 mg of losartan, and 106 to the placebo (an identical looking pill with no active medicine) once a day for 12 months. From the 197 (93%) participants who completed the study, primary outcome data were available for 171 (81%) participants.
The trial assessed the rate of whole brain shrinkage (i.e. atrophy) on MRI scan compared between participants on losartan and those on placebo. The researchers also examined differences in memory tests, day-to-day quality of life and in a subgroup of participants, changes in levels of vascular damage to the brain as measured by MRI.
The study found that 12-months’ treatment with losartan in patients with clinically diagnosed and established mild-to-moderate probable Alzheimer’s disease did not significantly slow down the progression of AD.
Professor Pat Kehoe, Gestetner Professor of Translational Dementia Research at the University of Bristol, who led the trial, said: “With the current lack of effective treatments for Alzheimer’s disease (AD), this is an extremely disappointing result for participants, patients and researchers alike that losartan, although well tolerated, was not effective in reducing the rate of brain atrophy in people with clinically diagnosed AD in the 12 months it was given, especially after so much encouraging evidence to support the need for this trial.
“However, we cannot exclude the possibility, given other findings that are emerging, that losartan, or similar drugs, given to people earlier and for longer in their development of Alzheimer’s, such as folk with certain types of mild cognitive impairment, might still be protective.
“It is vitally important we continue to search for effective treatments for AD because with an ageing population there will continue to be many people diagnosed with the disease, which will greatly impact on our already overstretched health and social care costs and resources.”
The research team are now exploring options to carry out further studies using losartan or other ways of treating the same biochemical deficits losartan was chosen to address, particularly those that might be possible to target in people with even milder specific impairments that might be indicative of very early signs of developing AD.
The study was funded by an MRC and NIHR partnership created to support the evaluation of interventions with potential to make a step-change in the promotion of health, treatment of disease and improvement of rehabilitation or long-term care.
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Researchers at the National Institutes of Health have discovered a therapy that targets host cells rather than bacterial cells in treating bacterial pneumonia in rodents. The method involves white blood cells of the immune system called macrophages that eat bacteria, and a group of compounds that are naturally produced in mice and humans called epoxyeicosatrienoic acids or EETs. The research was published in the Journal of Clinical Investigation.
According to the World Health Organization, pneumonia caused by Streptococcus pneumoniae, or pneumococcal pneumonia, is the leading cause of pneumonia deaths worldwide each year. While physicians usually prescribe antibiotics to treat this severe lung infection, treatment is not always successful, and in some cases, the bacteria become resistant.
Matthew Edin, Ph.D., a scientist at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, wanted to find a way to augment the body’s immune system to resolve the infection.
To keep tissues healthy, EETs work to limit inflammation, but during infections caused by S. pneumoniae and other microorganisms, inflammation ramps up after lung cells induce certain substances that prompt macrophages to gobble up the bacteria. Edin and colleagues found that one way to get macrophages to eat more bacteria is to decrease the ability of EETs to do what they normally do, which is limit inflammation.
Edin led the team that found infection induces a protein called soluble epoxide hydrolase (sEH) that degrades EETs. In contrast, when sEH is blocked, EET levels skyrocket, hampering the macrophages’ ability to sense and eat bacteria. As a result, the bacteria continue to reproduce in the lung, which leads to severe lung infection and death.
At the other end of the spectrum, blocking EETs using a synthetic molecule called EEZE boosted the eating capacity of the macrophages, leading to reduced numbers of bacteria in the lungs of mice. The scientists saw the same result when they placed bacteria and macrophages harvested from lung and blood samples of human volunteers in test tubes at the NIEHS Clinical Research Unit.

Fat-free chocolate milk processed for the first time with high-pressure jet technology exhibits enhanced viscosity, stabilizing cocoa particles in the fluid and eliminating the need for adding a controversial emulsifier.
That’s the conclusion of a team of Penn State researchers, whose study suggests that the new technology can preclude the use of carrageenan in chocolate milk. The widely used food additive — which helps keep the liquid smooth and well-mixed even after days sitting on a store shelf — is not desired by many consumers, especially in organic chocolate milk.
Although the U.S. Food and Drug Administration has approved the use of carrageenan, concerns about its safety remain, according to team leader Federico Harte, professor of food science. He noted that some scientists believe that the additive — a compound extracted from red seaweed — can cause inflammation and digestive problems such as bloating and irritable bowel disease. As a result, the additive is banned in infant formula in the European Union.
“This research is not about being against carrageenan — it’s about consumers wanting clean food labels with only ingredients they recognize,” he said. “And carrageenan definitely is not something they want in chocolate milk. We know that USDA has considered banning it for organic chocolate milks. Our results indicate that would be possible.”
In the study, researchers thermally treated fat-free chocolate milk formulations containing skim milk, cocoa powder and sugar and then processed them using high-pressure jet technology from 125 to 500 megapascals. The viscosity, flow properties and stability of chocolate milks treated with high-pressure jets were compared with chocolate milks that did not undergo high-pressure jet processing, prepared both with and without adding carrageenan.
As expected, carrageenan-free chocolate milk exhibited immediate phase separation of the cocoa powder, whereas formulations containing carrageenan were stable for 14 days, with cocoa particles not dropping out of suspension. However, the researchers observed increased stability with increasing jet processing pressure, with maximum stability achieved when chocolate milk was processed at 500 megapascals.

A Rice University undergraduate student’s grit and talent paid off in a big way when she introduced the first synthesis of a rare and potentially potent molecule drawn from poppies.
Anavi Serna, a junior, spent the duration of a summer fellowship in the Rice lab of synthetic chemist László Kürtichasing a sequence that would produce setigerumine I, an alkaloid molecule found in trace amounts in the poppy family Papaveraceae.
That natural setigerumine is a molecule the researchers described as “obscure and elusive,” and so hard to isolate it’s difficult for labs to study the molecule as a possible precursor for drugs or other products. But it was an apt target for Kürti’s lab, which develops or simplifies chemical paths for the synthesis of pharmaceutical building blocks used in drug design and manufacture.
Ultimately, Serna and her mentor, Rice chemistry lecturer and corresponding author Juha Siitonen, produced the natural product in a three-step, room temperature process that started with oxidizing and rearranging a precursor molecule, noscapine, found in cough syrup.
Siitonen, who will become an assistant professor of organic chemistry at Aalto University in his native Finland in January, had been looking at setigerumine I, first isolated in 1993, and several other rare poppy extracts for a while.
“Because this molecule is isolated from poppies that also produce morphine, the likelihood that it has desirable biological properties is pretty significant,” Siitonen said. “We’ve been facing an opioid crisis for years now, so we clearly need better painkillers that are non-addictive. We don’t know if this is the one, because we’ve only just made it, but it might prove practical.”
The team’s paper appears in the journal Angewandte Chemie.

An effective and safe oral pill is welcome news for people at risk for blood clots, after a worldwide study led by McMaster University proved milvexian can be used with minimal side effects.
Milvexian is unique in that it works by targeting factor XIa, a clotting enzyme that causes dangerous thrombosis, blood clots, but is not vital for stopping bleeding from injuries.
Researchers compared milvexian with enoxaparin for prevention of blood clots in 1,242 patients from18 countries undergoing knee replacement surgery who were enrolled between June 2019 and February 2021.
They found that at a total daily dose of 100 mg or more, milvexian resulted in better clot protection but no increase in bleeding compared with enoxaparin, the control drug. Milvexian was evaluated in daily doses ranging from 25 to 400 mg; there was no increase in bleeding over this wide range of doses.
“The major side effect of current oral anti-clotting drugs is bleeding, and the fear of bleeding leads to their underuse. This sets the need for safer oral anticoagulants and that is where milvexian comes in,” said senior author Jeffrey Weitz.
He is a professor of medicine and biochemistry and biomedical sciences at McMaster. He is also the executive director of the Thrombosis and Atherosclerosis Research Institute of McMaster and Hamilton Health Sciences.
“Blood clots are responsible for 1 in 4 deaths worldwide. Anticoagulants (blood thinners) are a mainstay for the treatment and prevention of clots in veins and arteries and we urgently need safer oral medications to reduce the burden from what are often lifelong conditions.”
The study was published today in the New England Journal of Medicine and Weitz presented a summary of the findings at a late breaking session at the 2021 American Heart Association Scientific Sessions.
Weitz said that blood clots are the underlying cause of heart attack, stroke, deep vein thrombosis, and pulmonary embolism. Many of these conditions require lifelong anticoagulant treatment. Therefore, there is a need for safer oral anticoagulants like milvexian.
He said the study focused on patients undergoing knee replacement surgery because they are at high risk for postoperative blood clots and such clots can be readily identified with venograms, x-rays of the veins of the legs. Therefore, this patient population provides an ideal testing ground for new anticoagulants because effective and safe doses can be identified.
Weitz said his milvexian study is the first of several investigations of oral factor XIa inhibitors. The results of the other studies will likely be released next year.
Funding for the study was provided by the pharmaceutical firms Bristol Myers Squibb and Janssen Research and Development.
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